Pub Date : 2025-10-01Epub Date: 2025-07-14DOI: 10.1016/j.jphs.2025.07.003
Hiroe Toba , Denan Jin , Shinji Takai
Acute kidney injury is associated with not only high morbidity in the acute phase but also the development of chronic kidney disease (CKD). Recently, we found that suppression of secreted protein acidic and rich in cysteine (SPARC) exhibits renoprotective effects in acute ischemia/reperfusion (I/R) injury. The present study investigated the hypothesis that temporal suppression of SPARC in the early stages of I/R-injury might lead to the prevention of renal injury in the chronic phase. The left renal pedicle of male BALB/c mice was occluded for 45 min after right uninephrectomy and subsequently reperfused for 28 days. Small interfering RNA (siRNA) targeting SPARC was injected intravenously 1 day before and 3 days after I/R. Histological assessment revealed that SPARC knockdown by siRNA attenuated tubular injury, tubulointerstitial fibrosis, and the overexpression of 4-hydroxynonenal, a marker of lipid peroxidation. I/R-induced overexpression of a major source of superoxide NADPH oxidase, tumor necrosis factor-α, and matrix metalloproteinase-9 was suppressed by siRNA targeting SPARC. Treatment with siRNA targeting SPARC reduced the expression of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), which colocalizes with SPARC. In conclusion, SPARC might be a potential therapeutic target for preventing CKD development following acute I/R injury.
{"title":"Early temporal suppression of SPARC inhibits oxidative stress, inflammation, and fibrosis in the chronic phase after renal ischemia/reperfusion","authors":"Hiroe Toba , Denan Jin , Shinji Takai","doi":"10.1016/j.jphs.2025.07.003","DOIUrl":"10.1016/j.jphs.2025.07.003","url":null,"abstract":"<div><div>Acute kidney injury is associated with not only high morbidity in the acute phase but also the development of chronic kidney disease (CKD). Recently, we found that suppression of secreted protein acidic and rich in cysteine (SPARC) exhibits renoprotective effects in acute ischemia/reperfusion (I/R) injury. The present study investigated the hypothesis that temporal suppression of SPARC in the early stages of I/R-injury might lead to the prevention of renal injury in the chronic phase. The left renal pedicle of male BALB/c mice was occluded for 45 min after right uninephrectomy and subsequently reperfused for 28 days. Small interfering RNA (siRNA) targeting SPARC was injected intravenously 1 day before and 3 days after I/R. Histological assessment revealed that SPARC knockdown by siRNA attenuated tubular injury, tubulointerstitial fibrosis, and the overexpression of 4-hydroxynonenal, a marker of lipid peroxidation. I/R-induced overexpression of a major source of superoxide NADPH oxidase, tumor necrosis factor-α, and matrix metalloproteinase-9 was suppressed by siRNA targeting SPARC. Treatment with siRNA targeting SPARC reduced the expression of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), which colocalizes with SPARC. In conclusion, SPARC might be a potential therapeutic target for preventing CKD development following acute I/R injury.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 57-63"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Inwardly rectifying potassium 4.1 (Kir4.1) channels are predominantly expressed in astrocytes and considered to be involved in the pathogenesis of brain diseases, including depression and epilepsy. In the present study, we evaluated the effects of Kir4.1 channel inhibitors, VU0134992 and quinacrine, on lipopolysaccharide (LPS)-induced cognitive impairment to clarify the role of Kir4.1 channels in controlling cognitive functions. Male BALB/c mice were treated with LPS, with or without Kir4.1 channel inhibitors, for 7 days. Animals were then subjected to novel object recognition (NOR) and rota-rod tests. Immunohistochemical analyses of glia fibrillary acid protein (GFAP) and neuronal nuclei (NeuN) were also performed. Treatment of LPS clearly showed cognitive impairment in the NOR test, which accompanied elevated GFAP- and reduced NeuN-immunoreactivity in hippocampal CA1 and CA3 regions. VU0134992 and quinacrine significantly ameliorated LPS-induced cognitive impairment without affecting rota-rod performance. In addition, both Kir4.1 channel inhibitors suppressed LPS-induced astrocyte activation and attenuated neuronal damage in CA1 and CA3 regions. Furthermore, combined treatments of ANA-12, a TrkB receptor antagonist, with VU0134992 suppressed the ameliorative effects of VU0134992 on cognitive impairment and hippocampal neuronal damage. These results suggest that blockade of astrocytic Kir4.1 channels ameliorates neuroinflammatory cognitive impairment via BDNF/TrkB signaling pathway.
{"title":"Ameliorative effects of Kir4.1 channel inhibitors on lipopolysaccharide-induced cognitive impairment via BDNF/TrkB signaling pathway","authors":"Yuto Ishizaki , Saki Shimizu , Ayana Kusaka, Akane Yoshida, Naofumi Kunisawa, Yukihiro Ohno","doi":"10.1016/j.jphs.2025.07.002","DOIUrl":"10.1016/j.jphs.2025.07.002","url":null,"abstract":"<div><div>Inwardly rectifying potassium 4.1 (Kir4.1) channels are predominantly expressed in astrocytes and considered to be involved in the pathogenesis of brain diseases, including depression and epilepsy. In the present study, we evaluated the effects of Kir4.1 channel inhibitors, VU0134992 and quinacrine, on lipopolysaccharide (LPS)-induced cognitive impairment to clarify the role of Kir4.1 channels in controlling cognitive functions. Male BALB/c mice were treated with LPS, with or without Kir4.1 channel inhibitors, for 7 days. Animals were then subjected to novel object recognition (NOR) and rota-rod tests. Immunohistochemical analyses of glia fibrillary acid protein (GFAP) and neuronal nuclei (NeuN) were also performed. Treatment of LPS clearly showed cognitive impairment in the NOR test, which accompanied elevated GFAP- and reduced NeuN-immunoreactivity in hippocampal CA1 and CA3 regions. VU0134992 and quinacrine significantly ameliorated LPS-induced cognitive impairment without affecting rota-rod performance. In addition, both Kir4.1 channel inhibitors suppressed LPS-induced astrocyte activation and attenuated neuronal damage in CA1 and CA3 regions. Furthermore, combined treatments of ANA-12, a TrkB receptor antagonist, with VU0134992 suppressed the ameliorative effects of VU0134992 on cognitive impairment and hippocampal neuronal damage. These results suggest that blockade of astrocytic Kir4.1 channels ameliorates neuroinflammatory cognitive impairment via BDNF/TrkB signaling pathway.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 64-73"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144662538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), affecting nearly one-third of CKD patients. As CKD advances, it may progress to end-stage renal disease, necessitating dialysis or transplantation. Hyperglycemia-driven metabolic and hemodynamic disturbances contribute to oxidative stress, inflammation, and fibrosis. Since current treatments remain insufficient, novel therapeutic strategies are urgently needed to halt DN progression. Stachybotrys microspora triprenyl phenols (SMTPs), the focus of our research, exhibit anti-inflammatory properties and have shown therapeutic potential in various disease models. We aimed to evaluate the efficacy of SMTP-27 in a DN mouse model. DN was induced by removing the right kidney of db/db mice. The efficacy of SMTP-27 was determined by evaluating the renal function using urine and serum samples and morphological assessment of the kidney tissues. For deciphering the mechanism of action of SMTP-27, markers associated with inflammatory signaling pathways in the kidney were detected. SMTP-27 (0.03, 0.3, 3, 30 mg/kg) dose-dependently improved the renal function. In addition, it improved the mesangial matrix overproduction, podocyte injury, and renal tubule injury and exhibited anti-inflammatory activity in the kidneys of mice with DN. These results indicate the potential of SMTP-27 as a novel therapeutic strategy for DN.
{"title":"Therapeutic potential of SMTP-27 in attenuating diabetic nephropathy with anti-inflammatory activity","authors":"Keita Shibata , Taiki Awane , Takashi Takaki , Keiji Hasumi , Koji Nobe","doi":"10.1016/j.jphs.2025.07.006","DOIUrl":"10.1016/j.jphs.2025.07.006","url":null,"abstract":"<div><div>Diabetic nephropathy (DN) is a leading cause of chronic kidney disease (CKD), affecting nearly one-third of CKD patients. As CKD advances, it may progress to end-stage renal disease, necessitating dialysis or transplantation. Hyperglycemia-driven metabolic and hemodynamic disturbances contribute to oxidative stress, inflammation, and fibrosis. Since current treatments remain insufficient, novel therapeutic strategies are urgently needed to halt DN progression. <em>Stachybotrys microspora</em> triprenyl phenols (SMTPs), the focus of our research, exhibit anti-inflammatory properties and have shown therapeutic potential in various disease models. We aimed to evaluate the efficacy of SMTP-27 in a DN mouse model. DN was induced by removing the right kidney of <em>db/db</em> mice. The efficacy of SMTP-27 was determined by evaluating the renal function using urine and serum samples and morphological assessment of the kidney tissues. For deciphering the mechanism of action of SMTP-27, markers associated with inflammatory signaling pathways in the kidney were detected. SMTP-27 (0.03, 0.3, 3, 30 mg/kg) dose-dependently improved the renal function. In addition, it improved the mesangial matrix overproduction, podocyte injury, and renal tubule injury and exhibited anti-inflammatory activity in the kidneys of mice with DN. These results indicate the potential of SMTP-27 as a novel therapeutic strategy for DN.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 87-93"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144721582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-07-18DOI: 10.1016/j.jphs.2025.07.004
Zaiqiang Yu , Shihu Men , Kazuyuki Daitoku , Tadaatsu Imaizumi , Masahito Minakawa , Kazuhiko Seya
Despite being the most common adult heart valve disease in developed countries, no medicinal treatment exists for calcific aortic valve stenosis (CAS). We previously demonstrated that tumor necrosis factor (TNF)-α promotes aortic valve calcification (AVC) via the bone morphogenic protein (BMP) 2-alkaline phosphatase (ALP) pathway. In the present study, we aimed to investigate the effects of Kampo, a traditional Japanese herbal medicine, on TNF-α-induced AVC involving CAS progression. We confirmed that Oren-gedoku-to (OGT, 10–100 μg/mL) strongly and dose-relatedly inhibited HAVIC calcification induced by TNF-α (30 ng/mL). OGT significantly inhibited TNF-α-induced BMP2 expression, p65 NF-κB phosphorylation, and ALP activation in HAVICs. Notably, two crude drugs from OGT [Coptis rhizome (CR), and Phellodendron bark (PB)] exhibited inhibitory effects akin to those of OGT. Berberine, mainly contained in CR and PB, also inhibited TNF-α induced HAVIC calcification, BMP2 expression, and p65 NF-κB phosphorylation. Further, OGT significantly prevented accelerated AVC in spontaneously hypertensive rats in vivo. Our results suggest that OGT and its component, berberine, can effectively prevent AVC acceleration both in vitro and in vivo.
{"title":"Oren-gedoku-to inhibits calcification of human aortic valve interstitial cells in vitro and aortic valve in spontaneously hypertensive rats in vivo","authors":"Zaiqiang Yu , Shihu Men , Kazuyuki Daitoku , Tadaatsu Imaizumi , Masahito Minakawa , Kazuhiko Seya","doi":"10.1016/j.jphs.2025.07.004","DOIUrl":"10.1016/j.jphs.2025.07.004","url":null,"abstract":"<div><div>Despite being the most common adult heart valve disease in developed countries, no medicinal treatment exists for calcific aortic valve stenosis (CAS). We previously demonstrated that tumor necrosis factor (TNF)-α promotes aortic valve calcification (AVC) via the bone morphogenic protein (BMP) 2-alkaline phosphatase (ALP) pathway. In the present study, we aimed to investigate the effects of Kampo, a traditional Japanese herbal medicine, on TNF-α-induced AVC involving CAS progression. We confirmed that Oren-gedoku-to (OGT, 10–100 μg/mL) strongly and dose-relatedly inhibited HAVIC calcification induced by TNF-α (30 ng/mL). OGT significantly inhibited TNF-α-induced BMP2 expression, p65 NF-κB phosphorylation, and ALP activation in HAVICs. Notably, two crude drugs from OGT [<em>Coptis</em> rhizome (CR), and <em>Phellodendron</em> bark (PB)] exhibited inhibitory effects akin to those of OGT. Berberine, mainly contained in CR and PB, also inhibited TNF-α induced HAVIC calcification, BMP2 expression, and p65 NF-κB phosphorylation. Further, OGT significantly prevented accelerated AVC in spontaneously hypertensive rats <em>in vivo</em>. Our results suggest that OGT and its component, berberine, can effectively prevent AVC acceleration both <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 74-86"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-07-17DOI: 10.1016/j.jphs.2025.07.005
Yangmei Xie , Ming Wang , Binyuan Xu , Yiye Shao , Yinghui Chen
Background
Neuroinflammation contributes to cognitive deficits in status epilepticus (SE). The lncRNA Mir155hg has been identified as a key regulator of inflammation, but its role in SE remains unclear.
Methods
Mir155hg was knocked down using the adeno-associated virus (AAV) in the rat models of SE. Cognitive function and neuronal damage were assessed using Morris Water Maze and Nissl staining. Inflammatory cytokines (TNF-α, IL-1β) and NF-κB pathway activity were measured by Western blot. Mechanistic insights into Mir155hg-mediated NF-κB regulation were investigated via dual-luciferase assays and co-immunoprecipitation analysis.
Results
Our findings demonstrated that elevated level of Mir155hg was positively correlated with upregulation of TNF-α and IL-1β both in vivo and in vitro. Knockdown of Mir155hg reduced hippocampal inflammation and NF-κB activation. Mechanistically, Mir155hg acted as a competing endogenous RNA to sequester miR-155, thereby suppressing the expression of Socs1, an E3 ligase targeting NF-κB p65 for degradation. Co-immunoprecipitation analysis confirmed the interaction between NF-κB p65 and Socs1.
Conclusions
Mir155hg exacerbates SE-related neuroinflammation via the miR-155/Socs1/NF-κB axis. Targeting this pathway may mitigate SE-induced neuronal injury and cognitive deficits.
{"title":"LncRNA Mir155hg contributes to hippocampal injury in status epilepticus rats through miR-155/Socs1/NF-κΒ signaling axis","authors":"Yangmei Xie , Ming Wang , Binyuan Xu , Yiye Shao , Yinghui Chen","doi":"10.1016/j.jphs.2025.07.005","DOIUrl":"10.1016/j.jphs.2025.07.005","url":null,"abstract":"<div><h3>Background</h3><div>Neuroinflammation contributes to cognitive deficits in status epilepticus (SE). The lncRNA Mir155hg has been identified as a key regulator of inflammation, but its role in SE remains unclear.</div></div><div><h3>Methods</h3><div>Mir155hg was knocked down using the adeno-associated virus (AAV) in the rat models of SE. Cognitive function and neuronal damage were assessed using Morris Water Maze and Nissl staining. Inflammatory cytokines (TNF-α, IL-1β) and NF-κB pathway activity were measured by Western blot. Mechanistic insights into Mir155hg-mediated NF-κB regulation were investigated via dual-luciferase assays and co-immunoprecipitation analysis.</div></div><div><h3>Results</h3><div>Our findings demonstrated that elevated level of Mir155hg was positively correlated with upregulation of TNF-α and IL-1β both in vivo and in vitro. Knockdown of Mir155hg reduced hippocampal inflammation and NF-κB activation. Mechanistically, Mir155hg acted as a competing endogenous RNA to sequester miR-155, thereby suppressing the expression of Socs1, an E3 ligase targeting NF-κB p65 for degradation. Co-immunoprecipitation analysis confirmed the interaction between NF-κB p65 and Socs1.</div></div><div><h3>Conclusions</h3><div>Mir155hg exacerbates SE-related neuroinflammation via the miR-155/Socs1/NF-κB axis. Targeting this pathway may mitigate SE-induced neuronal injury and cognitive deficits.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 105-115"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144724137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-01Epub Date: 2025-08-08DOI: 10.1016/j.jphs.2025.08.001
Xiaoyan Ma , Yilizere Aibaidula , Chunzi Zhang , Shuwen Qi , Tuxia Pang , Juan Zhang , Wenhui Hou , Xiaoli Ma
Lactucin is a natural sesquiterpene lactone isolated from Cichorium glandulosum Boiss. et Huet (CG) has unique biological and pharmaceutical properties. This study was designed to investigate the mechanisms by which Lactucin inhibits lipid accumulation in free fatty acid (FFA)-treated HepG2 cells. We demonstrated that Lactucin exerts a protective effect against hepatic steatosis in vitro. In FFA-induced HepG2 cells, Lactucin effectively ameliorated lipid accumulation, oxidative stress, and mitochondrial dysfunction. Mechanistically, we showed that activation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL) by Lactucin promoted lipolysis and further enhanced fatty acid β-oxidation (FAβO) by increasing the activity of FAβO-related enzymes, thereby contributing to the reduction of lipid accumulation. Moreover, Lactucin activated autophagy and modulated the AMPK/mammalian target of rapamycin (mTOR) signaling pathway. Notably, we found that Lactucin-induced autophagy played a significant role in decreasing lipid droplet accumulation, suggesting it may be a key underlying mechanism. These findings, for the first time, provide new insights into the pharmaceutical mechanism of Lactucin in protecting against nonalcoholic fatty liver disease (NAFLD).
lacucin是一种天然的倍半萜内酯，从菊苣中分离得到。et Huet （CG）具有独特的生物学和药学特性。本研究旨在探讨乳酸蛋白抑制游离脂肪酸（FFA）处理的HepG2细胞脂质积累的机制。我们证明了乳酸蛋白在体外对肝脂肪变性有保护作用。在ffa诱导的HepG2细胞中，lacucin有效地改善了脂质积累、氧化应激和线粒体功能障碍。在机制上，我们发现乳酸蛋白激活amp激活的蛋白激酶（AMPK）和激素敏感脂肪酶（HSL）促进脂肪分解，并通过增加FAβO相关酶的活性进一步增强脂肪酸β氧化（FAβO），从而有助于减少脂质积累。此外，lacucin激活自噬并调节AMPK/哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。值得注意的是，我们发现乳酸素诱导的自噬在减少脂滴积累中起着重要作用，这可能是一个关键的潜在机制。这些发现首次为乳黄素预防非酒精性脂肪性肝病（NAFLD）的药物机制提供了新的见解。
{"title":"Lactucin alleviates lipid accumulation via AMPK-mediated autophagy and fatty acid β-oxidation in FFA-induced HepG2 cells","authors":"Xiaoyan Ma , Yilizere Aibaidula , Chunzi Zhang , Shuwen Qi , Tuxia Pang , Juan Zhang , Wenhui Hou , Xiaoli Ma","doi":"10.1016/j.jphs.2025.08.001","DOIUrl":"10.1016/j.jphs.2025.08.001","url":null,"abstract":"<div><div>Lactucin is a natural sesquiterpene lactone isolated from <em>Cichorium glandulosum</em> Boiss. et Huet (CG) has unique biological and pharmaceutical properties. This study was designed to investigate the mechanisms by which Lactucin inhibits lipid accumulation in free fatty acid (FFA)-treated HepG2 cells. We demonstrated that Lactucin exerts a protective effect against hepatic steatosis in vitro. In FFA-induced HepG2 cells, Lactucin effectively ameliorated lipid accumulation, oxidative stress, and mitochondrial dysfunction. Mechanistically, we showed that activation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL) by Lactucin promoted lipolysis and further enhanced fatty acid β-oxidation (FAβO) by increasing the activity of FAβO-related enzymes, thereby contributing to the reduction of lipid accumulation. Moreover, Lactucin activated autophagy and modulated the AMPK/mammalian target of rapamycin (mTOR) signaling pathway. Notably, we found that Lactucin-induced autophagy played a significant role in decreasing lipid droplet accumulation, suggesting it may be a key underlying mechanism. These findings, for the first time, provide new insights into the pharmaceutical mechanism of Lactucin in protecting against nonalcoholic fatty liver disease (NAFLD).</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 2","pages":"Pages 116-127"},"PeriodicalIF":2.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway is a major cellular defense mechanism against oxidative stress through the induction of antioxidant proteins. Chemical inducers of Nrf2 often exhibit anti-inflammatory properties. TPNA10168, originally identified as an Nrf2–ARE activator, has previously been shown to attenuate interferon-γ-induced inflammatory responses in BV-2 microglial cells in an Nrf2-independent manner. However, its anti-inflammatory effects on primary microglia remain unclear. In this study, TPNA10168 significantly suppressed the lipopolysaccharide (LPS)-induced expression of inflammatory genes, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in primary microglia. The anti-inflammatory effects of TPNA10168 persisted even after Nrf2 knockdown. Mechanistic analysis revealed that TPNA10168 inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB (NF-κB) p65 without affecting NF-κB nuclear translocation. These findings indicate that TPNA10168 attenuates microglial activation by inhibiting proinflammatory signaling pathways, in part through Nrf2-independent pathways, and is a promising compound for modulating neuroinflammation.
{"title":"TPNA10168, an Nrf2 activator, attenuates LPS-induced inflammation in microglia through modulation of MAPK and NF-κB pathways","authors":"Yasuhiko Izumi , Eri Koide , Fumika Kobayashi , Saori Ikawa , Midai Takayama , Kouya Yamaki , Norihiko Takeda , Takahiro Yamada , Masafumi Ueda , Toshiaki Kume , Yutaka Koyama","doi":"10.1016/j.jphs.2025.07.001","DOIUrl":"10.1016/j.jphs.2025.07.001","url":null,"abstract":"<div><div>The nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway is a major cellular defense mechanism against oxidative stress through the induction of antioxidant proteins. Chemical inducers of Nrf2 often exhibit anti-inflammatory properties. TPNA10168, originally identified as an Nrf2–ARE activator, has previously been shown to attenuate interferon-γ-induced inflammatory responses in BV-2 microglial cells in an Nrf2-independent manner. However, its anti-inflammatory effects on primary microglia remain unclear. In this study, TPNA10168 significantly suppressed the lipopolysaccharide (LPS)-induced expression of inflammatory genes, including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, in primary microglia. The anti-inflammatory effects of TPNA10168 persisted even after Nrf2 knockdown. Mechanistic analysis revealed that TPNA10168 inhibited LPS-induced phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-κB (NF-κB) p65 without affecting NF-κB nuclear translocation. These findings indicate that TPNA10168 attenuates microglial activation by inhibiting proinflammatory signaling pathways, in part through Nrf2-independent pathways, and is a promising compound for modulating neuroinflammation.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 35-43"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2025-06-16DOI: 10.1016/j.jphs.2025.06.003
Maha Habash , Zainab H. Almansour , Rasha K. Al-Akeel , Mohammad Bani Ismail , Duaa Althumairy , Hamad Abu Zahra , Tarek Hamdy Abd-Elhamid , Osama M. Ghogar , Mahmoud M. Ali , Mostafa K. Abd El-Aziz , Elham I. Sharab , Heba F. Khader , Amany Refaat Mahmoud , Fares E.M. Ali
Obstructive nephropathy is a chronic condition that causes progressive kidney damage due to inflammation, oxidative stress, necroptosis, and fibrosis. The present study aimed to evaluate the potential chemopreventive effect of infliximab (TNF-α inhibitor) or umbelliferone (UMB, a natural antioxidant) individually and together to treat unilateral ureter ligation (UUL)-induced interstitial renal fibrosis in rats. The therapeutic effects were assessed through renal function biomarkers, histopathology, fibrosis, inflammation, oxidative stress, and necroptosis. UUL-induced renal injury led to increased serum biomarkers (urea, creatinine, uric acid), inflammation markers (TNF-α, NF-κB, IKK), oxidative stress (elevated NADPH oxidase and MDA, reduced Nrf2/HO-1, GSH, SOD), and necroptosis (upregulated RIPK1/RIPK3/p-RIPK3/MLKL/caspase-8), with substantial collagen deposition and fibrosis. Treatment with infliximab and UMB showed preventive effects by suppressing TNF-α signaling, reducing oxidative stress, and boosting antioxidant defense. Combined therapy provided superior results by downregulating TNF-α/RIPK/Caspase-8 pathways, enhancing Nrf2/HO-1 activity, reducing fibrosis, and restoring renal structure and function. Computational docking confirmed the ability of UMB to interact with TNF-α and RIPK3/MLKL binding sites. In conclusion, the combination of infliximab and UMB offers a promising multi-targeted approach to treat obstructive nephropathy and related chronic kidney diseases and highlights its potential to modulate key pathways involved in kidney fibrosis.
{"title":"Down-regulation of TNF-α/RIPK/Caspase-8 axis by combined infliximab and umbelliferone prevents unilateral ureter ligation-induced interstitial renal fibrosis","authors":"Maha Habash , Zainab H. Almansour , Rasha K. Al-Akeel , Mohammad Bani Ismail , Duaa Althumairy , Hamad Abu Zahra , Tarek Hamdy Abd-Elhamid , Osama M. Ghogar , Mahmoud M. Ali , Mostafa K. Abd El-Aziz , Elham I. Sharab , Heba F. Khader , Amany Refaat Mahmoud , Fares E.M. Ali","doi":"10.1016/j.jphs.2025.06.003","DOIUrl":"10.1016/j.jphs.2025.06.003","url":null,"abstract":"<div><div>Obstructive nephropathy is a chronic condition that causes progressive kidney damage due to inflammation, oxidative stress, necroptosis, and fibrosis. The present study aimed to evaluate the potential chemopreventive effect of infliximab (TNF-α inhibitor) or umbelliferone (UMB, a natural antioxidant) individually and together to treat unilateral ureter ligation (UUL)-induced interstitial renal fibrosis in rats. The therapeutic effects were assessed through renal function biomarkers, histopathology, fibrosis, inflammation, oxidative stress, and necroptosis. UUL-induced renal injury led to increased serum biomarkers (urea, creatinine, uric acid), inflammation markers (TNF-α, NF-κB, IKK), oxidative stress (elevated NADPH oxidase and MDA, reduced Nrf2/HO-1, GSH, SOD), and necroptosis (upregulated RIPK1/RIPK3/p-RIPK3/MLKL/caspase-8), with substantial collagen deposition and fibrosis. Treatment with infliximab and UMB showed preventive effects by suppressing TNF-α signaling, reducing oxidative stress, and boosting antioxidant defense. Combined therapy provided superior results by downregulating TNF-α/RIPK/Caspase-8 pathways, enhancing Nrf2/HO-1 activity, reducing fibrosis, and restoring renal structure and function. Computational docking confirmed the ability of UMB to interact with TNF-α and RIPK3/MLKL binding sites. In conclusion, the combination of infliximab and UMB offers a promising multi-targeted approach to treat obstructive nephropathy and related chronic kidney diseases and highlights its potential to modulate key pathways involved in kidney fibrosis.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 8-20"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144331447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetic neuropathy (DN) affects more than 50 % of patients with diabetes mellitus (DM). With progression, it causes negative symptoms characterized by sensory numbness. However, no effective treatment drug has been approved for the negative symptoms of DN. In this study, Stachybotrys microspora triprenyl phenol-44D (SMTP-44D), previously reported to inhibit apoptosis and ameliorate axonal damage in immortalized mouse Schwann cells treated with high glucose, was evaluated in a DN mouse model. Streptozocin (STZ)-induced DM models were treated with SMTP-44D for 49 days starting 8 days after STZ administration of SMTP-44D, and effects on mechanical and thermal thresholds, blood flow, and conduction velocity were evaluated. Epoxyeicosatrienoic acid (EET)/dihydroxyeicosatrienoic acid (DHET) measurements in serum, morphological changes in the sciatic nerve, immunohistochemistry, and TUNEL staining were performed to elucidate the mechanism of action. SMTP-44D improved the 11,12-EET/DHET decrease in serum and blood flow in the sciatic nerve. It inhibited sciatic nerve apoptosis and alleviated myelin thinning, thereby preserving the conduction velocity and showing dose-dependent improvements in mechanical and thermal threshold elevation. A hypoglycemic effect with long-term administration is suggested based on the findings. In conclusion, SMTP-44D is a promising therapeutic agent against the negative symptoms of DN.
{"title":"SMTP-44D prevents negative symptoms of diabetic neuropathy by inhibiting sciatic nerve apoptosis","authors":"Ayaka Aoki , Keita Shibata , Ryosuke Shinouchi , Keiji Hasumi , Koji Nobe","doi":"10.1016/j.jphs.2025.06.006","DOIUrl":"10.1016/j.jphs.2025.06.006","url":null,"abstract":"<div><div>Diabetic neuropathy (DN) affects more than 50 % of patients with diabetes mellitus (DM). With progression, it causes negative symptoms characterized by sensory numbness. However, no effective treatment drug has been approved for the negative symptoms of DN. In this study, <em>Stachybotrys microspora</em> triprenyl phenol-44D (SMTP-44D), previously reported to inhibit apoptosis and ameliorate axonal damage in immortalized mouse Schwann cells treated with high glucose, was evaluated in a DN mouse model. Streptozocin (STZ)-induced DM models were treated with SMTP-44D for 49 days starting 8 days after STZ administration of SMTP-44D, and effects on mechanical and thermal thresholds, blood flow, and conduction velocity were evaluated. Epoxyeicosatrienoic acid (EET)/dihydroxyeicosatrienoic acid (DHET) measurements in serum, morphological changes in the sciatic nerve, immunohistochemistry, and TUNEL staining were performed to elucidate the mechanism of action. SMTP-44D improved the 11,12-EET/DHET decrease in serum and blood flow in the sciatic nerve. It inhibited sciatic nerve apoptosis and alleviated myelin thinning, thereby preserving the conduction velocity and showing dose-dependent improvements in mechanical and thermal threshold elevation. A hypoglycemic effect with long-term administration is suggested based on the findings. In conclusion, SMTP-44D is a promising therapeutic agent against the negative symptoms of DN.</div></div>","PeriodicalId":16786,"journal":{"name":"Journal of pharmacological sciences","volume":"159 1","pages":"Pages 25-34"},"PeriodicalIF":3.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号